Introduction

Top Introduction Polarity of the Placental... Monoamine Transporters Carnitine Transporter Transporters for... Sodium/Multivitamin Transporter Equilibrative Nucleoside... Folate Receptor and Folate... P-glycoprotein Organic Cation/Proton... Organic Cation Transporter... Prostaglandin Transporter Amino Acid Transporters Summary References

Placenta constitutes the sole link between the mother and the developing fetus and performs a multitude of functions that are essential for the maintenance of pregnancy and for normal development of the fetus. One of the major functions of the placenta is to mediate the transfer of nutrients from the mother to the fetus and to eliminate metabolic waste products from the fetus. This function is facilitated by various transporters that are expressed differentially in a polarized manner in the maternal-facing brush-border membrane and the fetal-facing basal membrane of the syncytiotrophoblast, a polarized epithelium and the functional unit of the placenta. The specificity of these transporters is, however, not restricted to their physiological substrates. Nonphysiological compounds bearing structural resemblance to the physiological substrates are recognized by these transporters as substrates. These compounds include therapeutic agents, environmental pollutants and toxins, and drugs of abuse. The distribution of these xenobiotics across the maternal-fetal interface is therefore influenced markedly by the transporters expressed in the placenta. Because many of these foreign substances are likely to have profound effects on the placenta and the fetus by their ability to interact with specific enzymes, receptors, transporters, and other regulatory proteins, a clear understanding of the cellular processes in the placenta that influence the access of these substances into the placenta and the fetus is of clinical, pharmacological, and therapeutic importance.

A variety of drugs are currently in therapeutic use in pregnancy for treatment of the mother and, to a lesser extent, the fetus. The potential of these pharmacologically active drugs to cross the physical separation between the maternal and fetal compartments is a major consideration in the judicial selection of these drugs for use in pregnancy. If the mother is the patient, transfer of the drugs into the placenta and the fetus may pose hazardous consequences to the fetus as well as the mother. On the other hand, if the fetus is the patient, transplacental transfer of the drugs from the mother to the fetus becomes an important determinant in the therapeutic efficacy of these drugs. In addition to the therapeutically useful drugs, several xenobiotics and drugs of abuse get access into the maternal circulation during pregnancy through either involuntary or voluntary exposure. The potential transfer of these compounds into the placenta and the fetus is also of serious health concern. One of the pivotal functions of the placenta is to provide essential nutrients to the developing fetus from the mother, but it is generally assumed that the placental barrier protects the fetus by restricting the passage of harmful chemicals. Unfortunately, this notion of the protective barrier function of the placenta may not be entirely correct. Placenta facilitates the transfer of nutrients and other physiological substances at the maternal-fetal interface via specific transporters. But, the specificity of these transporters in the placenta is not strictly restricted to their physiological substrates. Xenobiotics that bear significant structural similarity to the physiological substrates have the potential to be recognized by the transporters expressed in the placenta. Thus the placental transporters play a crucial role in the distribution of pharmacological agents, xenobiotics, and abusable drugs across the maternal-fetal interface. Furthermore, because these compounds compete with the physiological substrates of the placental transporters, they are also likely to interfere with the transplacental delivery of nutrients from the mother to the fetus and consequently produce deleterious effects on the growth and development of the fetus.

	Polarity of the Placental Syncytiotrophoblast and Its Relevance to the Transplacental Transfer of Physiological Substances and Xenobiotics

Top Introduction Polarity of the Placental... Monoamine Transporters Carnitine Transporter Transporters for... Sodium/Multivitamin Transporter Equilibrative Nucleoside... Folate Receptor and Folate... P-glycoprotein Organic Cation/Proton... Organic Cation Transporter... Prostaglandin Transporter Amino Acid Transporters Summary References

Placenta constitutes the sole structural barrier at the maternal-fetal interface. It is a specialized organ of fetal origin that carries out a multitude of functions obligatory for normal fetal development. These functions include transfer of nutrients from the mother to the fetus, removal of metabolic waste products from the fetus, and secretion of a variety of steroid and peptide hormones into the maternal and/or fetal circulations. All these processes occur vectorially, and this is made possible by the polarized nature of the syncytiotrophoblast, the functional unit of the placenta (Sideri et al., 1983; Williams et al., 1989). The syncytiotrophoblast arises from the fusion of cytotrophoblast stem cells and forms a true syncytium with no lateral cell membranes (Fig. 1). The plasma membrane of the syncytiotrophoblast is polarized, consisting of the brush-border membrane that is in direct contact with maternal blood and the basal membrane that faces the fetal circulation. These two domains of the syncytiotrophoblast plasma membrane are functionally and structurally distinct. The brush-border membrane possesses a microvillous structure that effectively amplifies the surface area, whereas the basal membrane lacks this structural organization. These two membranes are further differentiated from each other by their protein composition. Various enzymes, hormone receptors, and transporters are differentially distributed between the brush-border membrane and the basal membrane. In the context of this review focusing on the distribution of drugs across the maternal-fetal interface, the differential localization of various transporters in the maternal-facing brush-border membrane versus the fetal-facing basal membrane is central to understanding how drugs are handled by the syncytiotrophoblast and how their distribution in the maternal side versus the fetal side of this polarized epithelium is affected. Table 1 lists the placental transporters that are relevant to the distribution of drugs across the placenta and also provides information on the polarized distribution of these transporters in the brush-border and basal membranes. Most of these transporters have specific physiological substrates but also transport several structurally similar xenobiotics. For some of the transporters, however, there are no known physiological substrates. Only xenobiotics have been shown to be transported via these transporters. It is tempting to speculate that these transporters function exclusively in the handling of foreign molecules, but the possibility exists that these transporters do function in the transport of physiological substrates that have not yet been identified. The direction of transport, i.e., influx into the syncytiotrophoblast or efflux out of the syncytiotrophoblast, is determined by the magnitude of the ionic gradient driving forces and the substrate concentration gradients, because most of these transporters can function in either direction under appropriate driving forces. One notable exception to this is P-glycoprotein that functions exclusively in the efflux of its substrates from the cells.

View larger version (113K): [in this window] [in a new window]   Fig. 1.   A schematic representation of the maternal-fetal interface in the placenta. ST, syncytiotrophoblast; CT, cytotrophoblast; FV, fetal blood vessel. (Adapted from Moe, 1995.)

	Monoamine Transporters

Top Introduction Polarity of the Placental... Monoamine Transporters Carnitine Transporter Transporters for... Sodium/Multivitamin Transporter Equilibrative Nucleoside... Folate Receptor and Folate... P-glycoprotein Organic Cation/Proton... Organic Cation Transporter... Prostaglandin Transporter Amino Acid Transporters Summary References

Placenta expresses three different monoamine transporters, namely the serotonin transporter (SERT), norepinephrine transporter (NET), and extraneuronal monoamine transporter (OCT3). SERT and NET are expressed in the brush-border membrane (Balkovetz et al., 1989; Ramamoorthy et al., 1993). Both of them are dependent on transmembrane Na⁺ and Cl gradients. The physiological substrates for these transporters are serotonin (SERT) and dopamine and norepinephrine (NET). But, these two transporters are also capable of transporting amphetamine and its derivatives (Ramamoorthy et al., 1995). The affinity of amphetamines is, however, much higher for NET than for SERT. Even though cocaine and tricyclic and nontricyclic antidepressants are known to interact with SERT and/or NET, these compounds bind to the transporters with high affinity and are not translocated across the membrane. Therefore, SERT and NET are expected to mediate concentrative accumulation of amphetamines inside the syncytiotrophoblast by Na⁺- and Cl-coupled active uptake into the cells from the maternal circulation. But, the transfer of cocaine and tricyclic and nontricyclic antidepressants across the brush-border membrane is not mediated by these transporters. There is evidence to suggest that the expression and/or activity of SERT and NET in the placenta is subject to regulation. SERT expression in placental trophoblast cells is up-regulated by cAMP, staurosporine, tyrosine kinase inhibitors, epidermal growth factor, and interleukin-1 (Ganapathy and Leibach, 1995; Kekuda et al., 2000). Recent animal studies have shown that the expression of NET in the placenta is regulated by cocaine exposure (Shearman and Meyer, 1999). Interestingly, there is a differential influence of cocaine exposure during pregnancy on the expression of NET in the placenta and in the fetal brain. A continuous exposure of pregnant rats to cocaine for three days late in pregnancy increases the expression of NET in the placenta without any noticeable effect on the expression of NET in the fetal brain (Shearman and Meyer, 1999). The underlying mechanism for the regulation of NET expression in the placenta upon cocaine exposure appears to be the drug-induced increase in catecholamines, which might up-regulate NET expression via activation of -adrenoceptors coupled with the elevation of cAMP levels within the trophoblast cells.

In contrast to SERT and NET, OCT3 is a Na⁺- and Cl-independent monoamine transporter (Kekuda et al., 1998; Wu et al., 1998a). Based on the transport function and primary structure, OCT3 belongs to a family of organic cation transporters (Koepsell et al., 1999). Recent evidence indicates that OCT3 is identical with the extraneuronal monoamine transporter (uptake₂) that has been described functionally as a Na⁺-and Cl-independent transport system for monoamines (Grundemann et al., 1998; Wu et al., 1998a). The distinctive characteristics of the extraneuronal monoamine transporter include the transport of dopamine and norepinephrine with low affinity, lack of requirement for Na⁺ or Cl for transport function, and sensitivity to inhibition by steroids (Trendelenburg, 1988). This transporter was originally named uptake₂ to differentiate it from uptake₁ which is the Na⁺- and Cl-coupled norepinephrine transporter (NET) expressed in noradrenergic neurons. Thus, placenta expresses uptake₁ (NET) as well as uptake₂ (OCT3). The physiological substrates for OCT3 are the monoamines serotonin, dopamine, norepinephrine, and histamine. But, several xenobiotics including amphetamines, the neurotoxin 1-methyl-4-phenylpyridinium, and the antidepressants imipramine and desipramine interact with OCT3. The actual transport via OCT3 has been demonstrated for the neurotoxin 1-methyl-4-phenylpyridinium (Wu et al., 1998a) and the K⁺-channel blocker tetraethylammonium (Kekuda et al., 1998). We speculate that amphetamines, imipramine, and desipramine are also transportable substrates for OCT3. Other potential substrates for OCT3 include clonidine, cimetidine, and amiloride. The substrate specificity of OCT3 is distinct from that of OCT1 and OCT2, two of the closely related members of the organic cation transporter family (Grundemann et al., 1999). However, OCT1 and OCT2 are expressed primarily in the kidney and liver (Koepsell et al., 1999; Zhang et al., 1998). There is no evidence of expression of OCT1 and OCT2 in the placenta (Wu et al., 1998a). The transport mechanism is, however, similar for OCT1, OCT2, and OCT3. All three transporters accept organic cations as substrates and the driving force for the transport process is the membrane potential. OCT3 is expressed most predominantly in the placenta, but its membrane localization in the syncytiotrophoblast has not been established. However, based on the functional evidence indicating the presence of a Na⁺-independent clearing mechanism for norepinephrine from the fetal circulation across the placental basal membrane (Bzoskie et al., 1995), OCT3 is likely to be located in the placental basal membrane.

	Carnitine Transporter

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The Na⁺-dependent high-affinity carnitine transporter is expressed in the placental brush-border membrane (Roque et al., 1996). The physiological function of this transporter is to mediate the delivery of carnitine from the maternal circulation into the fetal circulation. Although the presence of the carnitine transporter in the brush-border membrane provides the mechanism for the entry of maternal carnitine into the syncytiotrophoblast, the mechanism responsible for the exit of carnitine across the basal membrane remains unknown. The relevance of the carnitine transporter to drug distribution across the placenta is the observation that this transporter also mediates the transport of several pharmacologically active drugs (Huang et al., 1999; Ohashi et al., 1999; Wu et al., 1999; Ganapathy et al., 2000). The drugs, whose transport via the carnitine transporter have been demonstrated directly by uptake measurements, include tetraethylammonium, quinidine, verapamil, pyrilamine, and the -lactam antibiotic cephaloridine. In addition, acetylcarnitine and propionylcarnitine, which are currently in clinical trials for the treatment of various neurological disorders such as Alzheimer's disease and diabetic neuropathy, are also high-affinity substrates for this transporter (Wu et al., 1999). Indirect evidence from competition studies exists for the transport of several other drugs by this transporter. This includes a wide spectrum of -lactam antibiotics containing quaternary nitrogen, the sulfonylurea glibenclamide, abusable drugs such as amphetamines, and antidepressants (imipramine and desipramine). Molecular cloning studies have shown that the carnitine transporter is a member of a drug transporter gene family consisting of transporters for a variety of organic cations and organic anions (Tamai et al., 1998; Wu et al., 1998b; Koepsell et al., 1999). It is therefore not surprising that the carnitine transporter, also known as OCTN2, is capable of mediating the transport of drugs. There are some interesting features regarding the transport function of OCTN2. Although OCTN2 can transport various substrates that are either zwitterionic or cationic, the transport of zwitterions occurs in a Na⁺-dependent manner, whereas the transport of cations occurs in a Na⁺-independent manner (Wu et al., 1999). Even more interesting are the findings that some mutations in OCTN2 exert differential effects on the zwitterion transport function and the cation transport function (Seth et al., 1999). This implies that the protein domains responsible for the transport of zwitterionic substrates are different from those responsible for the transport of cationic substrates. These findings are of clinical relevance because mutations in OCTN2 are the cause for the genetic disorder called primary carnitine deficiency. Although each and every mutation in these patients is expected to result in the loss of the carnitine (a zwitterion) transport function, all of these mutations may not interfere with the cation transport function. Because some of the drugs recognized by OCTN2 are zwitterions (e.g., cephaloridine), the mutations in patients with primary carnitine deficiency are expected to interfere with the ability of OCTN2 to transport these drugs. The relevance of these observations to the OCTN2-mediated transfer of drugs across the placenta is readily apparent. Because the placenta is of fetal origin, the maternal-fetal distribution of drugs that are substrates for OCTN2 is likely to be affected significantly in pregnancies with embryos that are homozygous or heterozygous for primary carnitine deficiency. In addition, the influence of OCTN2 mutations on the placental distribution of drugs is expected to differ between the zwitterionic drugs and the cationic drugs depending on the individual mutation.

	Transporters for Monocarboxylates and Dicarboxylates

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Placenta expresses transport processes for the handling of monocarboxylates (e.g., lactate and pyruvate) and dicarboxylates (e.g., succinate and -ketoglutarate). The placental brush-border membrane possesses the monocarboxylate transporter (Balkovetz et al., 1988) as well as the dicarboxylate transporter (Ganapathy et al., 1988b). Functional studies with intact placenta and the choriocarcinoma cell line BeWo have suggested that the placental basal membrane may also possess the monocarboxylate transport mechanism (Carstensen et al., 1983; Piquard et al., 1990; Utoguchi et al., 1999). In humans, there is evidence for net transfer of lactate from the fetus to the mother at least at the end of pregnancy (Piquard et al., 1990). In perfused human placenta, lactate transfer rates have been found to be the same in both maternal-to-fetal and fetal-to-maternal directions (Illsley et al., 1986). However, because the circulating lactate levels are always higher in the fetus than in the mother, a net transfer of lactate in the fetal-to-maternal direction is likely to occur in vivo. There are several isoforms of monocarboxylate transporters and dicarboxylate transporters. Available evidence indicates that placenta expresses the monocarboxylate transporters MCT1, MCT3, MCT4, MCT5, and MCT7 (Price et al., 1998) and the dicarboxylate transporter NaDC3 (Wang et al., 2000). There is no information available at present regarding the identity of the MCT isoforms expressed in the brush-border membrane and the basal membrane. MCTs are H⁺-coupled and mediate an electroneutral cotransport of H⁺ and monocarboxylates (Poole and Halestrap, 1993). Because there is no significant H⁺ gradient across the brush-border membrane as well as the basal membrane, the direction of transport is dictated primarily by the direction of the transmembrane concentration gradients for the monocarboxylate substrates. NaDC3, on the other hand, is Na⁺-coupled and mediates an electrogenic cotransport of Na⁺ and dicarboxylates. Therefore, under physiological conditions, NaDC3 is expected to function in the entry of dicarboxylates from the maternal circulation into the syncytiotrophoblast. The specificity of MCTs and NaDC3 is not restricted to their physiological substrates. Several weak organic acids such as benzoic acid, acetic acid, acetylsalicylic acid (aspirin), and the anionic antibiotic cefdinir are transported by MCTs (Tsuji and Tamai, 1996; Utoguchi et al., 1999). Similarly, the glutamate transport blocker trans-pyrrolidine-2,4-dicarboxylate is a transportable substrate for NaDC3 (W. Huang, H. Wang, R. Kekuda, Y. J. Fei, A. Friedrich, J. Wang, S. J. Conway, R. S. Cameron, F. H. Leibach, and V. Ganapathy, unpublished data). Therefore, the MCTs and NaDC3 in the placenta have the potential to influence the distribution of several drugs and xenobiotics across the maternal-fetal interface.

	Sodium/Multivitamin Transporter

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A Na⁺-dependent active transport system is present in human placental brush-border membrane vesicles that is specific for the water-soluble vitamins biotin and pantothenate (Grassl, 1992a,b). This transport system has been recently cloned and functionally characterized (Wang et al., 1999). This transporter mediates the Na⁺-dependent electrogenic transport of biotin, pantothenate, and lipoate and hence is called sodium/multivitamin transporter (SMVT). The brush-border location of SMVT in the syncytiotrophoblast indicates that SMVT mediates the entry of these vitamins into the placenta from the maternal blood. All three known physiological substrates for SMVT are anions, and it is likely that these anions, following their SMVT-mediated concentrative accumulation inside the syncytiotrophoblast, exit across the basal membrane. The molecular identity of the exit transporter has not been established. We speculate that an anion transporter may be responsible for this exit process. The relevance of SMVT to transplacental transfer of drugs is indicated by the findings that long-term therapy with anticonvulsant drugs is associated with biotin deficiency (Krause et al., 1985), which suggests an interaction between the intestinal biotin transport system and anticonvulsant drugs. Because the placenta and intestine express SMVT (Prasad et al., 1999), the underlying mechanism for biotin deficiency induced by anticonvulsant drugs may be that these drugs compete with physiological substrates for transport via SMVT. This is supported by recent findings in our laboratory that the transport of biotin and pantothenate via SMVT is inhibited by the anticonvulsant drugs carbamazepine and primidone (P. D. Prasad, W. Huang, and V. Ganapathy, unpublished data). It is therefore likely that the placental entry of these anticonvulsant drugs is facilitated by SMVT across the placental brush-border membrane.

	Equilibrative Nucleoside Transporters

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Two different Na⁺-independent equilibrative nucleoside transporters (ENT1 and ENT2) have been cloned from placenta (Griffiths et al., 1997a,b). Both of them mediate the transport of purine and pyrimidine nucleosides such as adenosine and uridine but differ in their sensitivity to inhibition by nitrobenzylthioinosine. ENT1 is sensitive to inhibition, whereas ENT2 is relatively insensitive to inhibition. Immunolocalization studies have shown that the placental brush-border membrane expresses ENT1 (Barros et al., 1995). The membrane localization of ENT2 in the placenta is not known. ENT1 and ENT2 are energy-independent transporters and, therefore, capable of facilitating only equilibrative, not concentrative, transport of nucleosides across the membrane. Both the transporters are targets for the coronary vasodilators dilazep and dipyridamole, which bind to these transporters and block their transport function. A number of anticancer nucleoside analogs (e.g., cladribine, cytarabine, gemcitrabine, and fludarabine) are transportable substrates for ENT1 and ENT2 (Griffiths et al., 1997a,b). There is also evidence showing that the antiviral agents dideoxyinosine and dideoxycytidine are low-affinity substrates for ENT1 (Domin et al., 1993). Because functional studies have established that equilibrative nucleoside transporters are expressed in the placental brush-border membrane as well as basal membrane (Barros et al., 1995), these transporters are expected to facilitate the transfer of these nucleoside analogs across the placenta from the mother to the fetus.

	Folate Receptor and Folate Transporter

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Maternal-to-fetal transfer of the water-soluble vitamin folate across the placenta is mediated by the combined function of the folate receptor and the folate transporter. The folate receptor is located in the brush-border membrane. It is a glycosylphosphatidylinositol-anchored protein present on the exoplasmic surface of the membrane and is in direct contact with maternal blood (Antony, 1996). It binds folate present in maternal blood and transfers it into the cytoplasm of the syncytiotrophoblast via receptor-mediated endocytosis. Among the three different isoforms of the folate receptor known to exist in mammalian tissues, only the -isoform is expressed in the syncytiotrophoblast (Prasad et al., 1994). The exit of folate across the fetal-facing basal membrane is facilitated by the folate transporter (FOLT1) (Prasad et al., 1995). FOLT1 operates in a pH dependent manner and the molecular mechanism is likely to be an exchange between folate and the hydroxyl ion. The differential localization of the folate receptor in the brush-border membrane and FOLT1 in the basalolateral membrane has been demonstrated by immunodetection with respective antibodies with BeWo cells (a placental trophoblast cell line) grown on permeable supports (Chancy et al., 2000). N⁵-Methyltetrahydrofolate is the most predominant form of folate in the maternal circulation and thus is the physiological substrate for the folate receptor and FOLT1 in the placenta. However, both proteins interact with a variety of antifolates such as methotrexate. Antifolates are used as therapeutic agents in the treatment of cancer and immune disorders. The placental transport process involving the folate receptor and FOLT1 is likely to facilitate the placental transfer of these drugs from the mother to the fetus.

	P-glycoprotein

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P-glycoprotein is the product of the multidrug resistance gene MDR1. It is expressed in the placental trophoblast layer and is located in the brush-border membrane (Cordon-Cardo et al., 1989; Nakamura et al., 1997). The function of this protein is to mediate active efflux of lipophilic xenobiotics from the cell and the driving force for this active process comes from ATP hydrolysis. This transport protein possesses ATPase activity that is activated by various drugs recognized by the transport protein. P-glycoprotein-mediated transport occurs unidirectionally facilitating the efflux, and not the influx, of the substrates due to the asymmetrical membrane topology of the protein. The ATP-binding site and the hydrolytic catalytic site reside on the cytoplasmic side of the membrane, and the hydrolysis of ATP on the cytoplasmic side is coupled to active efflux of substrates out of the cell. Interestingly, the only physiological function of P-glycoprotein appears to be the removal of xenobiotics from the cell, thus protecting the cell from the potential toxic effects of xenobiotics. This transporter is expressed not only in the placenta but also in the intestinal tract, kidney, liver, and blood-brain barrier. The plasma membranes of absorptive cells of the placenta, intestine and kidney, hepatocytes in the liver and endothelial cells of the blood-brain barrier exhibit polarity. P-glycoprotein is expressed specifically in the brush-border membrane of the absorptive cells of the placenta, intestine and kidney, in the canalicular membrane of the hepatocytes and in the luminal membrane of the endothelial cells of the blood-brain barrier. This subcellular localization is ideal for the physiological function of the P-glycoprotein where it can mediate the elimination of xenobiotics from the body. It appears that this drug efflux transporter may have evolved as a protective mechanism in animals against the potential toxic effects of environmental toxins and other xenobiotics. Animal studies with P-glycoprotein-knockout mice have provided strong supporting evidence for an important role of the placental P-glycoprotein in protecting the fetus from potentially harmful and therapeutic agents (Lankas et al., 1998; Smit et al., 1999). Intravenous administration of the P-glycoprotein substrates digoxin, saquinavir, and taxol to pregnant animals leads to a severalfold greater transfer of these drugs across the placenta into the fetus in P-glycoprotein knockout mice than in wild-type mice. P-glycoprotein has a broad substrate specificity, accepting a large number of chemically diverse compounds as substrates. The substrates of P-glycoprotein include anticancer drugs (e.g., vincristine, vinblastine, anthracyclines, etoposide, taxol, and mithramycin), cytotoxic agents (e.g., colchicine and emetine), HIV protease inhibitors (e.g., sequinavir, indinavir, and ritonavir) (Ambudkar et al., 1999), and abusable drugs (e.g., morphine) (Letrent et al., 1999). Because of the vectorial function of P-glycoprotein in the placental syncytiotrophoblast, these drugs are prevented from transplacental transfer from the mother to the fetus. One group of P-glycoprotein substrates that is relevant to the placenta is steroids. Progesterone interacts with P-glycoprotein and inhibits the transporter-mediated efflux of drugs (Yang et al., 1989). But, progesterone itself is not a transportable substrate for P-glycoprotein (Ueda et al., 1992). Placenta produces large quantities of progesterone, and therefore one would expect this steroid to suppress the potency of P-glycoprotein to eliminate xenobiotics from the placenta. The physiological and pharmacological implications of such a potential influence of progesterone on the P-glycoprotein function remain to be investigated.

	Organic Cation/Proton Antiporters

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At least two distinct organic cation/proton antiporters have been described in placental brush-border membrane vesicles (Ganapathy et al., 1988a; Prasad et al., 1992). The molecular identity of these antiporters remains unknown. In the kidney and intestine, organic cation/proton antiporters located in the brush-border membrane of the epithelial cells are expected to function in the removal of cationic organic compounds from the cell facilitated by the favorable transmembrane pH gradient known to occur across this membrane under physiological conditions (Lucas et al., 1976; Aronson, 1983). There is no evidence for such a pH gradient across the placental brush-border membrane. This membrane however contains an active H⁺-pump (Simon et al., 1992) that may function in concert with the organic cation/proton antiporters to facilitate the efflux of cationic drugs from the syncytiotrophoblast. The two antiporters exhibit overlapping substrate specificity, and their substrates include cimetidine, clonidine, amiloride, imipramine, and benzamil. These are mostly water-soluble organic cations, in contrast to the substrates of P-glycoprotein, which are mostly lipophilic organic cations. Thus, the substrate specificity of the organic cation/proton antiporters in the placenta complement with that of P-glycoprotein. Together, these transporters have the potential to handle a large number of structurally diverse chemicals.

	Organic Cation Transporter OCTN1

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OCTN1, a novel organic cation transporter belonging to the family of organic cation and anion transporters, is expressed in placenta (Wu et al., 2000). OCTN1 transports a variety of cationic drugs including tetraethylammonium, quinidine, and verapamil. It has been suggested by Yabuuchi et al. (1999) that OCTN1 may be an organic cation/proton antiporter. It is, however, unlikely because although OCTN1 is expressed abundantly in placenta, tetraethylammonium, which is a substrate for OCTN1, is not recognized by the organic cation/proton antiporters described in this tissue (Ganapathy et al., 1988a; Prasad et al., 1992). In addition, the membrane localization of OCTN1 in the syncytiotrophoblast has not been established.

	Prostaglandin Transporter

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Functional evidence exists for the transfer of prostaglandins across the placenta (Glance et al., 1986). Northern blot analysis has shown that placenta expresses mRNA for the recently cloned prostaglandin transporter PGT (Lu et al., 1996). The membrane localization of PGT in placenta is not known. Prostaglandins and thromboxanes that are known substrates for PGT are physiological substances with profound influences on placental circulation and function. A number of synthetic prostaglandin E₁ or E₂ analogs have been used to treat glaucoma, terminate pregnancy, and provide gastric protection (Lu et al., 1996). In addition to the prostaglandin analogs, furosemide, a widely used diuretic, is also a transportable substrate for PGT. Therefore, expression of PGT in placenta indicates a role for this transporter in the placental handling of these compounds and also in the pregnancy-dependent alterations in their pharmacokinetics. PGT is an electrogenic obligatory anion exchanger (Chan et al., 1998), which suggests that this transporter functions in the entry of prostaglandins and thromboxanes into the syncytiotrophoblast.

	Amino Acid Transporters

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Several amino acid transporters are expressed in placenta with differential localization in the brush-border membrane and the basal membrane of the syncytiotrophoblast (Moe, 1995). Although the physiological function of these transporters is to mediate the placental handling of amino acids including their transplacental transfer, some of these transporters may potentially be involved in the transport of pharmacologically active drugs with a structural resemblance to amino acids. It is known that several therapeutic agents such as gabapentin (an antiepileptic drug), arginine analogs (inhibitors of nitric oxide synthases), and thyroid hormone mimics are substrates for specific amino acid transporters. Therefore, the placental amino acid transporters are potential players in the distribution of drugs across the maternal-fetal interface.

	Summary

Top Introduction Polarity of the Placental... Monoamine Transporters Carnitine Transporter Transporters for... Sodium/Multivitamin Transporter Equilibrative Nucleoside... Folate Receptor and Folate... P-glycoprotein Organic Cation/Proton... Organic Cation Transporter... Prostaglandin Transporter Amino Acid Transporters Summary References

Placenta expresses several transporters that are relevant to drug distribution across the maternal-fetal interface. Most of these transporters perform vital physiological functions in facilitating the transfer of nutrients and other normal metabolites across the placenta, but many of them also recognize xenobiotics as substrates due to structural resemblance to the physiological substrates. As a consequence, these transporters also mediate the transfer of xenobiotics across the placenta. Some transporters in the placenta may function exclusively as xenobiotic transporters. With the increasing knowledge of the substrate specificity of various placental transporters, it is evident that placenta is not an effective barrier in protecting the developing fetus against harmful xenobiotics. It is important to recognize that although some transporters do function in preventing the entry of xenobiotics into the fetoplacental unit, several transporters actually facilitate the entry of xenobiotics. A thorough understanding of the role of various transporters in the placenta in the handling of xenobiotics across the maternal-fetal interface is essential to evaluate the pharmacological and toxicological potential of therapeutic agents, drugs of abuse, and other xenobiotics used by the mother during pregnancy.